CETP genotype predicts increased mortality in statin-treated men with proven cardiovascular disease: an adverse pharmacogenetic interaction.
OBJECTIVE
Inhibition of cholesteryl ester transfer protein (CETP) increases HDL-cholesterol. However, its combination with statins may increase mortality by factors incompletely understood. We previously observed that patients with intrinsically low CETP levels (carriers of the TaqIB-B2 allele) may have less benefit from statin therapy, and here tested this pharmacogenetic hypothesis on long-term outcomes.


RESULTS
We performed a 10-year follow-up analysis in 812 coronary artery disease (CAD) patients (REGRESS cohort), treated with statins after an initial 2-year study period. Carriers of TaqIB-B2 showed reduced CETP levels and higher HDL-cholesterol (P < 0.001 for both). Despite these lower CETP and higher HDL-cholesterol levels, hazard ratios per B2 copy were 1.59 (P = 0.01) for atherosclerotic disease death, 1.53 (P = 0.03) for ischaemic heart disease death, and 1.30 (P = 0.04) for all-cause mortality. Haplotype-effects analysis provided even stronger basis for the genetics involved: one risk-haplotype was identified that was highly significantly associated with these endpoints.


CONCLUSIONS
In statin-treated male CAD patients, genetic variation conferring low CETP levels is associated with increased 10-year mortality. This suggests that efficacy of statin therapy to reduce cardiovascular risk depends on CETP genotype and associated CETP plasma levels. This effect may need consideration when administering CETP inhibition to CAD patients.
Regieli
Jakub J
JJ
Juliuscenter for Health Sciences and Primary Care, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
Jukema
J Wouter
JW
Grobbee
Diederick E
DE
Kastelein
John J P
JJ
Kuivenhoven
Jan Albert
JA
Zwinderman
Aeilko H
AH
van der Graaf
Yolanda
Y
Bots
Michiel L
ML
Doevendans
Pieter A
PA
D000483:Alleles; D000924:Anticholesteremic Agents / Q000009:adverse effects*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D008076:Cholesterol, HDL / Q000187:drug effects / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D005838:Genotype; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D017035:Pravastatin / Q000627:therapeutic use; D011237:Predictive Value of Tests; D011804:Quinolines / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic
D000924:Anticholesteremic Agents; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D011804:Quinolines; C483909:torcetrapib; D017035:Pravastatin